Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• Asthma is a disease which is becoming more prevalent and is the most common disease of childhood. It can be identified by recurrent wheeze and intermittent air flow limitation. Despite many advances in its understanding, said pathology remains a poorly understood and often poorly treated disease. Previously, contraction of airway smooth muscles has been regarded as the most important feature of asthma. Recently there has been a marked change in the way asthma is managed, stemming from the fact that asthma is recognized as a chronic inflammatory disease. Uncontrolled airway inflammation may lead to mucosal damage and structural changes giving irreversible narrowing of the airways and fibrosis of the lung tissue. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
• the symptoms may be controlled by first generation ⁇ 2 -adrenoceptor agonists such as salbutamol, fenoterol and terbutalin or second generation ones such as formoterol and salmeterol (long-acting ⁇ 2 -agonists) which overcome the disadvantage of the short duration of action particularly for patients with nocturnal asthma.
• Prophylactic therapy instead, is typically provided by corticosteroids such as beclometasone dipropionate, fluticasone propionate mometasone furoate and budesonide.
• COPD chronic obstructive pulmonary disease
• COPD chronic obstructive pulmonary disease
• Chronic bronchitis is characterized by excessive secretion of bronchial mucus, whereas emphysema denotes abnormal, permanent enlargement of air spaces distal to the terminal bronchiole, with destruction of their walls and without obvious fibrosis (American Thoracic Society). Each condition is treated as specific diseases.
• Chronic obstructive bronchiolitis is due to obstruction of the peripheral airways as a result of inflammation in the bronchioles.
• Drugs intended for the treatment of lung diseases such as asthma and COPD are currently administered by pulmonary delivery which relies on inhalation of an aerosol through the mouth and throat so that the drug substance can reach the lung. They can be administered as aqueous or hydroalcoholic formulations through a nebuliser, as dry powders by means of Dry Powder Inhalers or in halogenated hydrocarbon propellants.
• the propellant-based systems require suitable pressurized metered-dose inhalers (pMDIs) which release a metered dose of medicine upon each actuation.
• Complicated therapy with different medications and devices may lead to poor compliance of the patients, so to under-treatment and, in turn, negative impact on their quality of life. This is dramatically evident in the case of long-term management of chronic asthma, in particular with prophylactic treatments, such as inhaled steroids, which do not give immediate symptom relief.
• Recent therapeutic strategy is aimed at both controlling the symptoms and reducing the inflammation by fixed combinations of a long-acting ⁇ 2 -agonist and a corticosteroid.
• a combination containing formoterol and budesonide in form of dry powder is currently on the market under the trade name of Symbicort® and each single dose is administered twice-daily. Each inhalation delivers a nominal dose of 6 microg of rac-formoterol fumarate and either 100 or 200 microg of budesonide.
• ⁇ 2 -agonist present in said combinations are under racemic form.
• formoterol is a mixture of (R,R)- and (S,S)-enantiomers, wherein the bronchodilator activity resides in the (R,R)-one while the other one is practically inactive; salmeterol instead is a mixture of (R)- and (S)-enantiomers with the latter one much less effective than the former (Waldeck B Gen Pharmac.1996, 27, 575-580).
• a combination of a ⁇ 2 -agonist and a steroid which: i) while keeping the rapid onset of action, has a longer duration of action in such a way as that the formulation can be administered once a day so delaying the possible appearance of tolerance towards the ⁇ 2 -agonist and with a great improvement of the compliance of patients, in particular of those with chronic and nocturnal asthma; ii) allows to reduce the dose of corticosteroid.
• 2(1H)-quinolone derivatives have been disclosed in the past, for instance in EP 147719 and WO 00/75114, and characterized as potent long lasting bronchodilating agents useful for the treatment or prophylaxis of various chronic obstructive pulmonary disease.
• a medicament comprising a particular 2(1H)-quinolinone derivative LABA and a corticosteroid for the treatment of inflammatory or obstructive airways diseases has been recently disclosed in WO 02/45703.
• JP 09-309830 referred to its use as an anti-inflammatory agent by inhalation but even in this case, a broad generic range of doses was reported, i.e. from 1 to 20 ⁇ g, for example about 3 to 10 ⁇ g.
• TA 2005 caused a dose-dependent increase in heart rate, tremor and pulmonary function and a decrease in plasma potassium. According to the authors, the maximum no adverse effect dose of TA 2005 was 9.6 ⁇ g. A very large therapeutic window between 0.8 and 9.6 ⁇ g has been therefore suggested, but an efficacious and safe dose has not been identified.
• the present invention provides a medicament comprising, separately or together: 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl-2(1H)-quinolinone (compound A), and/or a physiologically acceptable salt and/or solvate thereof and a corticosteroid useful for the treatment of the inflammatory or obstructive airways diseases preferably selected from the group of budesonide and its epimers, beclometasone dipropionate, flunisolide, fluticasone propionate, ciclesonide, triamcinolone acetonide, rofleponide palmitate and mometasone furoate (compounds B), for simultaneous, sequential or separate administration in the prophylaxis or treatment of an inflammatory or obstructive airways disease such as asthma or COPD.
• an inflammatory or obstructive airways disease such as asthma
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising, together, effective amounts of (A) as hereinbefore defined and a corticosteroid, as hereinbefore defined, optionally together with at least one pharmaceutically acceptable carrier.
• the invention further provides the use of (A) as hereinbefore defined in combination with a corticosteroid, as hereinbefore defined in the preparation of a pharmaceutical composition or a kit for the prophylaxis or treatment, by simultaneous, sequential or separate administration of (A) and the corticosteroid, of any inflammatory or obstructive airways disease.
• the synergistic increment of the anti-inflammatory effects may be attributed to the strengthening of those mediated via the ⁇ 2 -adrenoreceptor, i.e. the decrease in the inflammatory cytokine tumour necrosis factor- ⁇ (TNF ⁇ ) release and the increase of the anti-inflammatory cytokine interleukin-10 (IL-10), which in turn depend on the stereochemistry of the compound.
• TNF ⁇ inflammatory cytokine tumour necrosis factor- ⁇
• IL-10 interleukin-10
• the present invention provides a medicament wherein the compound (A) is present in the combination as hydrochloride salt (TA 2005) in a suitable amount to provide a daily dose comprised between 0.5 and 8 ⁇ g, advantageously between 1 and 6 ⁇ g, preferably between 2 and 4 ⁇ g, for simultaneous, sequential or separate administration once or twice daily, preferably once daily, in the treatment of an inflammatory or obstructive airways disease such as asthma or COPD.
• TA 2005 hydrochloride salt
• Compound (A) is preferably used in the form of its hydrochloride salt (TA 2005).
• Suitable physiological salts of compound (A) include bromide, sulphate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, mesilate, ascorbate, salicylate, acetate, succinate, lactate, glutarate or gluconate.
• Solvates of salts such as hydrates, emihydrates or others with pharmaceutically acceptable organic solvents are also comprised in the invention.
• the medicament of the invention can comprise anticholinergic atropine-like derivatives such as ipratropium bromide, oxitropium bromide, tiotropium bromide, in order to provide a medicament particularly effective for the treatment of COPD.
• anticholinergic atropine-like derivatives such as ipratropium bromide, oxitropium bromide, tiotropium bromide, in order to provide a medicament particularly effective for the treatment of COPD.
• ratios in which the two active substances, i.e. the compound (A) and the corticosteroid, may be used in the combination of the invention are variable.
• the ratios by weight which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various steroids and their different potencies.
• the pharmaceutical combinations according to the invention may contain compound (A) and the corticosteroid in ratios by weight ranging from 1: 3200 to 1: 10.
• the ratio by weights ranges from 1:1600 to 1:10, preferably from 1:500 to 1:50, for fluticasone propionate from 1:1000 to 1:10, preferably from 1:500 to 1:20, for mometasone furoate from 1:800 to 1:20, preferably from 1:200 to 1:50 and for the 22R-epimer of budesonide from 1:320 to 1:20, preferably from 1:160 to 1:40.
• the intended dose regimen is twice or once daily, preferably once daily, where the suitable daily dose of compound (A) is advantageously the range of 0.5 to 8 ⁇ g, preferably of 1 to 6 ⁇ g, more preferably of 2 to 4 ⁇ g and the suitable daily dose of the steroid is in the range of 10 to 2000 ⁇ g.
• the suitable dose is in the range of 50 to 1600 ⁇ g, for fluticasone propionate in the range of 25 to 1000 ⁇ g, for mometasone furoate in the range of 25 to 400 ⁇ g and for the 22R-epimer of budesonide in the range of 20 to 160 ⁇ g.
• the dose regimen will strongly depend on the patient (age, weight etc.) and the severity of the disease.
• Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
• a diluent or carrier generally non-toxic and chemically inert to the medicaments, e.g. lactose or any other additive suitable for improving the respirable fraction can be added to the powdered medicament.
• Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain both the active ingredient of the combination of the invention in solution or in dispersed form or one component dissolved and the other dispersed.
• the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants.
• the propellant-free inhalable formulations comprising the combination of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers such as Respimat® .
• Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment.
• Inflammatory or obstructive airways diseases to which the claimed combinations are applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
• Treatment of asthma is also to be understood as embracing treatment of subjects, e. g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern.
• Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e. g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy.
• Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e. g. between the hours of about 4 to 6 a.m., i. e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
• inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD) including chronic bronchitis and emphysema, bronchiolitis, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
• ALI acute lung injury
• ARDS adult respiratory distress syndrome
• COAD chronic obstructive pulmonary, airways or lung disease
• COAD chronic obstructive pulmonary, airways or lung disease
• pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
• pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
• aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
• aluminosis anthracosis
• asbestosis chalicosis
• ptilosis ptilosis
• siderosis silicosis
• tobacosis and byssinosis.
• the invention further provides a pharmaceutical kit comprising compound (A) and a corticosteroid, as hereinbefore described, in separate unit dosage forms, said forms being suitable for administration of (A) and the corticosteroid in effective amounts.
• a kit suitably further comprises one or more inhalation devices for administration of (A) and the corticosteroid.
• the kit may comprise one or more dry powder inhalation devices adapted to deliver dry powder from a capsule, together with capsules containing a dry powder comprising a dosage unit of (A) and capsules containing a dry powder comprising a dosage unit of the corticosteroid.
• the kit may comprise a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising (A) and a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising the corticosteroid.
• the kit may comprise a metered dose inhaler containing an aerosol comprising (A) in a propellant and a metered dose inhaler containing an aerosol comprising the corticosteroid in a propellant.
• Example 1 In vitro assay on human U-937 derived macrophage cell line of the anti-inflammatory efficacy of the combination of the invention
• U-937 cells are cultured and macrophage-differentiated by 10 ng/ml phorbol myristate acetate for 48 hours.
• LPS lipopolysaccharide
• cAMP cyclic adenosine 3',5'-monophosphate
• TNF ⁇ and IL-10 in the culture medium are determined by a commercial available ELISA kit, while cAMP is determined by a commercial 3 H-cAMP analysis kit.
• TA 2005 is used in concentration ranges of 10 -11 to 3x10 -6 M while three different concentrations of a corticosteroid is used.
• Example 2 In vivo assay of the anti-inflammatory efficacy of the combination of the invention in a Sephadex induced lung oedema model
• the Sephadex model of lung oedema in the rat is a model which leads to inflammatory cell infiltration and interstitial oedema.
• Male rats (225-250 g) are housed for one week before initiating experiments. Food and water are supplied at libitum.
• Rats are dosed intratracheally with vehicle or Sephadex beads (5 mg/ml) at a dose volume of 1 ml/kg under anesthesia.
• TA 2005 and a corticosteroid are dissolved/suspended in distilled water and administered intratracheally suitably diluted in the Sephadex suspension.
• Rats are killed 24 h post-administration, the lungs are removed and the lung wet weights determined. Percent inhibition of the Sephadex-induced oedema is then determined.
• Example 3 Formulation for metered dose inhaler comprising TA 2005 and 22R-budesonide
• a HFA formulation for metered dose inhaler was prepared with the composition as follows: Components Amounts Per unit Nominal dose mg % ⁇ g TA 2005 0.15 0.0016 w/v 1 22R-budesonide 12.00 0.127 w/v 80 Ethanol 1650.0 15 w/w - HC1 0.1 M 3.30 0.03 w/w - Water 220.05 2.0 w/w HFA 134a q.s. to 9.45 ml 9114.5 - -
• the formulation 120 actuations/canister, overage of 30 actuations was filled in aluminum canisters having the internal surface coated with Teflon (two stage pressure filling) and fitted with a metering valve having a 63 ⁇ l metering chamber.
• Example 4 Powder formulation for dry powder inhaler comprising TA 2005 and 22R-budesonide
• a powder formulation for dry powder inhaler was prepared with the composition as follows: Components Amounts Per unit dose mg % TA 2005 0.001 22R-budesonide 0.160 Alpha-lactose monohydrate 212-355 ⁇ m 8.8551 88.6 Pre-blend 0.9839 10 Total weight 10
• the pre-blend mixture was obtained as follows: alpha-lactose monohydrate SpheroLac 100 (Meggle EP D30) with a starting particle size of 50 to 400 ⁇ m and magnesium stearate with a starting particle size of 3 to 35 ⁇ m in the ratio 98:2 w/w were co-milled in a jet mill apparatus.

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